OBJECTIVE To evaluate the cost-effectiveness of rezivertinib versus gefitinib as first-line treatment for epidermal growth factor receptor （EGFR） mutation-positive advanced non-small cell lung cancer （NSCLC） from the perspective of the Chinese healthcare system. METHODS A Markov model was constructed based on the REZOR trial data， with a cycle length of 3 weeks and a study duration of 5 years. Both costs and health outcomes were discounted at an annual rate of 5%. A cost-utility analysis was conducted using 3 times China’s 2024 per capita gross domestic product as the willingness-to-pay （WTP） threshold. The economic differences between the rezivertinib regimen versus the gefitinib regimen were evaluated using the incremental cost- effectiveness ratio （ICER） and incremental net monetary benefit （INMB）. Sensitivity and scenario analyses were performed to verify the robustness of the model. RESULTS Compared to the gefitinib regimen， the rezivertinib regimen saved 225 310.47 yuan and gained an additional 0.57 quality- adjusted life years （QALYs）， resulting in an ICER of －395 562.80 yuan/QALY， which was much lower than the WTP threshold of this study， indicating that rezivertinib had an absolute economic advantage. The INMB analysis （389 041.26 yuan） further validated this conclusion. One-way and probabilistic sensitivity analyses confirmed the robustness of the model. Scenario analysis， incorporating a 15% reduction in drug prices and adjustments to the utility values for progression free survival and progression disease， yielded consistent results with the base case analysis. CONCLUSIONS Compared to gefitinib， rezivertinib as a first-line treatment for EGFR mutation-positive advanced NSCLC has an absolute economic advantage.

OBJECTIVES: Long-term treatment of olanzapine, the most widely-prescribed second-generation antipsychotic, remarkably increases the risk of non-alcoholic fatty liver disease (NAFLD), whereas the mechanism for olanzapine-induced NAFLD remains unknown. Excessive hepatic fat accumulation is the basis for the pathogenesis of NAFLD, which results from the disturbance of TG metabolism in the liver. Apolipoprotein A5 (ApoA5) is a key regulator for TG metabolism in vivo that promotes TG accumulation in hepatocytes, thereby resulting in the development of NAFLD. However, there are no data indicating the role of apoA5 in olanzapine-induced NAFLD. Therefore, this study aims to investigate the role of apoA5 in olanzapine-induced NAFLD. METHODS: This study was carried out via animal studies, cell experiment, and ApoA5 gene knockdown experiment. Six-week-old male C57BL/6J mice were randomized into a control group, a low-dose group, and a high-dose group, which were treated by 10% DMSO, 3 mg/(kg·d) olanzapine, and 6 mg/(kg·d) olanzapine, respectively for 8 weeks. The lipid levels in plasma, liver function indexes, and expression levels of ApoA5 were detected. HepG2 cells were treated with 0.1% DMSO (control group), 25 μmol/L olanzapine (low-dose group), 50 μmol/L olanzapine (medium-dose group), and 100 μmol/L olanzapine (high-dose group) for 24 h. HepG2 cells pretreated with 100 μmol/L olanzapine were transfected with siRNA and scrambled siRNA (negative control), respectively. We observed the changes in lipid droplets within liver tissues and cells using oil red O staining and fat deposition in liver tissues using HE staining. The mRNA and protein levels of ApoA5 were determined by real-time PCR and Western blotting, respectively. RESULTS: After intervention with 3 and 6 mg/(kg·d) olanzapine for 8 weeks, there was no significant difference in body weight among the 3 groups (P>0.05). Olanzapine dose-dependently increased the plasma TG, ALT and AST levels, and reduced plasma ApoA5 levels (all P<0.05), whereas there was no significant difference in plasma cholesterol (HDL-C, LDL-C, and TC) levels among the 3 groups (all P>0.05). Olanzapine dose-dependently up-regulated ApoA5 protein levels in liver tissues (all P<0.05), but there was no significant change in ApoA5 mRNA expression among groups (P>0.05). In the control group, the structure of liver tissues was intact, the morphology of liver cells was regular, and only a few scattered lipid droplets were found in the cells. In the olanzapine-treated group, there was a large amount of lipid deposition in hepatocytes, and cells were balloon-like and filled with lipid droplet vacuoles. The nucleus located at the edge of cell, and the number of lipid droplets was increased significantly, especially in the high-dose group. Likewise, when HepG2 cells were treated with olanzapine for 24 h, the number and size of lipid droplets were significantly elevated in a dose-dependent manner. Moreover, olanzapine dose-dependently up-regulated ApoA5 protein levels in HepG2 cells (all P<0.05), but there was no significant difference in ApoA5 mRNA expression among groups (P>0.05). Compared with the HepG2 cells transfected with scrambled siRNA, the number and size of lipid droplets in HepG2 cells transfected with ApoA5 siRNA were significantly reduced. CONCLUSIONS The short-term intervention of olanzapine does not significantly increase body weight of mice, but it can directly induce hypertriglyceridemia and NAFLD in mice. Olanzapine inhibits hepatic apoA5 secretion but does not affect hepatic apoA5 synthesis, resulting in the pathogenesis of NAFLD. Inhibition of apoA5 secretion plays a key role in the development of olanzapine-related NAFLD, which may serve as an intervention target for this disease.
Animals ; Apolipoprotein A-V/genetics* ; Body Weight ; Dimethyl Sulfoxide/metabolism* ; Liver/metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease/chemically induced* ; Olanzapine/metabolism* ; RNA, Messenger/metabolism* ; RNA, Small Interfering ; Triglycerides

Objective:To investigate the application of pulse contour cardiac output (PiCCO) monitoring technology in fluid resuscitation of severe burn patients in shock period.Methods:From January 2015 to December 2019, 33 patients with severe burns who were hospitalized in Guangzhou Red Cross Hospital, meeting the inclusion criteria, were recruited into a retrospective cohort study with their clinical information collected. The patients were divided into PiCCO monitoring group with 15 cases (13 males and 2 females, aged (43±13) years) and routine monitoring group with 18 cases (14 males and 4 females, aged (39±9) years) according to the monitoring method used. After admission, all the patients were rehydrated following the rehydration formula of the Third Military Medical University for shock period. In routine monitoring group, the fluid resuscitation of patients was performed by monitoring indicators such as urine volume and blood pressure, while PiCCO monitoring was performed among patients in PiCCO monitoring group, and their fluid resuscitation was guided by the patient′s condition and the hemodynamic parameters (without pursuing normal levels of the parameters) of PiCCO monitoring on the basis of normal monitoring indicators in routine monitoring group. The colloids coefficients, the electrolyte coefficients (compared with the corresponding rehydration formula value of 0.75 mL·kg -1·% total body surface area (TBSA) -1 of the Third Military Medical University for shock period during the first 24 h post injury), the total rehydration coefficients, and the urine volumes during the first and second 24 h post injury, the lactic acid level, the base excess level, and the oxygenation index at admission and 24, 48 h after admission, and the mechanical ventilation time, the wound healing time, and the death ratio of patients in the two groups were recorded. The cardiac index, the global end-diastolic volume index (GEDVI), the intrathoracic blood volume index (ITBVI), the extravascular lung water index (EVLWI), and the systemic vascular resistance index (SVRI) of patients in PiCCO monitoring group at post injury hour 24, 48, and 72 and the abnormal cases were recorded. Data were statistically analyzed with Fisher′s exact probability test, independent-sample or one-sample t test, analysis of variance for repeated measurement, and Bonferroni correction. Results:During the first 24 h post injury, the colloids coefficients of patients in PiCCO monitoring group was (0.69±0.15) mL·kg -1·%TBSA -1, which was significantly less than (0.85±0.16) mL·kg -1·%TBSA -1 in routine monitoring group ( t=-2.612, P<0.05). Compared with the rehydration formula value of the Third Military Medical University for shock period, only the colloids coefficient of patients in routine monitoring group during the first 24 h post injury was significantly increased ( t=2.847, P<0.05). There were no statistically significant differences between the two groups in the colloids coefficients of patients during the second 24 h post injury, or the electrolyte coefficients, the total rehydration coefficients, the urine volumes of patients during the first and the second 24 h post injury ( t=0.579, -0.011, 0.417, -1.321, -0.137, 0.031, 1.348, P>0.05). The lactic acid level, the base excess level, the oxygenation index of patients at admission and 48 h after admission, and the oxygenation index of patients at 24 h after admission between the two groups were similar ( t=-1.837, 0.620, 0.292, -1.792, 1.912, -0.167, 1.695, P>0.05). The levels of lactic acid and base excess of patients in PiCCO monitoring group were (4.8±1.4) and (1.2±5.5)mmol/L, respectively, which were significantly better than (7.0±1.5) and (-2.8±3.0) mmol/L in routine monitoring group at 24 h after admission ( t=-3.904, 2.562, P<0.05 or P<0.01). There were no statistically significant differences between the two groups in the mechanical ventilation time or the wound healing time of patients ( t=-0.699, -0.697, P>0.05), or the death ratio of patients ( P>0.05). In PiCCO monitoring group, the GEDVI, and the ITBVI of patients were lower than the normal low values at post injury hour 24 and 48, which were in the normal range at post injury hour 72; the cardiac index of patients increased gradually and recovered to normal at post injury hour 48; the SVRI of patients increased significantly at post injury hour 24 and then gradually decreased to normal; the EVLWI average of patients at all time points post injury were less than 10 mL/kg. At post injury hour 24, most of the hemodynamic parameters of more than or equal to 8/15 patients in PiCCO monitoring group were abnormal, and the abnormal proportion decreased later. Conclusions:On the basis of traditional monitoring indicators, the use of PiCCO monitoring technology combined with the patient′s condition (without pursuing normal levels of the parameters) in guiding the fluid resuscitation in severe burn patients can reduce the usage of colloid and better improve tissue perfusion, with the resuscitation effect being better than conventional monitoring.